Pediatric Neurology Pearls
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- Phebe Sims
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1 Pediatric Neurology Pearls CHILDHOOD ACUTE ONSET NEUROPSYCHIATRIC SYMPTOMS A U D R E Y F O S T E R - B A R B E R, M D P H D P E D I A T R I C B R A I N C E N T E R O U T P A T I E N T D I R E C T O R, C H I L D N E U R O L O G Y R E S I D E N C Y D I R E C T O R, V I C E C H A I R N E U R O L O G Y U C S F K E N D A L L N A S H, M D P E D I A T R I C B R A I N C E N T E R I N P A T I E N T D I R E C T O R, A S S O C. M E D I C A L D I R E C T O R P H Y S I C I A N N E T W O R K D E V T. B E N I O F F C H I L D R E N S H O S P I T A L S Case #1 8yo boy, with tics and Obsessive Compulsive (OC) symptoms Onset of simple tics 2 years prior- sniff, snort, deep breathe, tapping fingers, palilalia Some obsessive character to tics, even out movements, repeat word a certain #of times to make it right In the last month some behavior issues- easy temper, yelling at sib, won t touch doorknobs or drawer handles Query- is this PANDAS? No ADHD signs or concerns Eating and Sleeping well Doing well at school No seizures Tics present for 2 years, vary in severity, often worse with illness or with stress No recent illness symptoms Throat culture done by Pediatrician, positive for Group A Strep (GAS), given antibiotics after 10 days of antibiotics tics improved, then worsened again a few weeks later No change in behavior issues, ocd symptoms
2 PMH- born at term with duodenal atresia, largyngeal cleft s/p repair Development- normal milestones, bright child, aa bit anxious but social and active in sports FH- Mother with Hashimoto s thyroiditis, history of anxiety, Father with history of a mood disorder SH- lives with mother and sibling, parents divorcing Dx-Tourette Syndrome or chronic tic disorder, OCD tendency Return to clinic 6 months later with concern for Explosive worsening of behavior, moody, more OCD symptoms Tics not worse, though a few new tics added to his repertoire No associated illness, primary doctor tested for Strep by throat culture and mycoplasma by antibodies, both negative Did receive a Flu vaccine a few weeks to a month prior New stressors- mother with new partner moving in, with partner s child Mother would prefer a PANDAS diagnosis, rather than a diagnosis of tic disorder with mood disorder PANDAS seems to have a clear treatment, whereas the others would be a chronic disorder Recommend- cognitive behavioral therapy (CBT), no antibiotics 6 months later, ongoing CBT with some benefit for behavior and OCD symptoms Tics still present, wax and wane Seen by Integrative Medicine doctor- Extensive Testing-zinc, heavy metal, strep culture, MTHFR polymorphism, autoimmune screen (ANA, DS-DNA) all negative -myocoplasma IgG+, Lyme Ab equivocal -Cunningham panel interpreted as abnormal -treated with 3 months of Azithromycin, patient self d/c d at 2 months due to GI distress
3 Why did PANDAS come up here? During the 2 months on antibiotics no tic worsening, OCD was better already with therapy Mother now not so sure about a PANDAS diagnosis, but feels antibiotics are benign so will consider them if symptoms worsen (child refused antibiotic prophylaxis) Plans to avoid escalation to immune therapy that was recommended- IVIg and or pheresis Declined other neurologic work up (MRI and LP) because doing too well Classic for Childhood Tic disorder- -tics onset prepubertal, vary in type, wax and wane over time -associated OCD (up to 50 % of patients) -bilineal inheritance (tics, adhd, anxiety, or ocd in both parents) Family Concerns -FH autoimmune disease -hope for something treatable -difficulty of proving associated infection, of attributing cause/effect of antibiotic therapy -common idea in the lay community, with integrative health providers History behind PANDAS 1980s- psychiatrists noted subset of patients with OCD who had a severe, abrupt onset of symptoms Temporal association with infectious triggers- strep, varicella, mycoplasma, influenza, EBV, Lyme Initially called PITANDS- Pediatric infection triggered autoimmune neurologic and psychiatric disorder Researchers chose to focus on GAS infection due to ease of documentation of infection and connection to known molecular mimicry in Sydenham s Chorealabeled PANDAS PANDAS- defined 1998 PANDAS- pediatric autoimmune neurologic disorder associated with Strep Presence of OCD and or tics- severe, interfere with patient s ability to function Age of onset 3yo to puberty Acute onset, episodic (relapsing remitting) Temporally related to GAS infection Other associated neurologic (choreiform movements) and behavioral abnormalities (sleep disturbance, enuresis, anxiety, lability, insomnia) Swedo, SE. J Child and Adol Psychpharm, Feb 25(1)
4 Defining a GAS infection is tricky Pediatric Acute onset Neuropsychiatric Syndrome 25% of the pediatric population has + strep culture without immune reaction (carrier) ASO and DNAse B titers can remain elevated for months (up to 12 mo in >50 % of kids s/p symptomatic infection) By age 12 years >98% of the population have positive titers PANDAS research dx requires flare associated with + culture and antibody evidence of appropriate rise in titer over time, at least twice (very rarely used clinically- diagnosis most often given with single positive culture) Blackburn, J. Seminars in Ped Neuro. 12: Consensus meeting Back to the idea that multiple infections can trigger a CNS response- PANS Mechanism may be molecular mimicry as with Strep (pseudo-autoimmune response- Ab to strep also reacts to neuronal antigens) Assume also other inflammatory mechanisms Primary focus on OCD symptoms, with other associated symptoms secondary- behaviors and movements PANS PANS clinic experience 15 Abrupt, dramatic onset of OCD or severe food restriction behavior Concurrent neuropsychiatric symptoms: 2/7 Anxiety Emotional lability Irritability, aggression, oppositional Behavioral regression Deterioration in school performance Sensory and motor abnormalities-tics, chorea Somatic symptomsinsomnia, enuresis Research clinic, must fulfill research definition exactly 84% documented prior illness, only 17% Strep Primary symptom OCD or eating d/o Tics 26%, chorea 15% Many with severe compulsions and mood issues, 1/3 with psychosis Higher rate of maternal autoimmune disease, strong FH of mood disorder Chang, K., Frankovich, J Journal of Child and Adol Psychopharmacology, 25(1): 2015.
5 Diagnostic Assessment for PANS Is the Cunningham panel helpful? Recommend full medical and family history, detailed neuro exam Note mild hypotonia and chorea sometimes seen, no other specific serious neurologic signs or symptoms (no seizures, no delirium, no focal findings) Strep test, other infectious titers, autoimmune labs Commercial antibody panel- Cunningham Panel, Moleculara Labs -serum testing, Elisa -anti-dopamine receptor D1 and D2L -anti-lysoganglioside GM1 -anti-tubulin Serum studies of autoantibodies Sensitivity individual biomarkers for PANS dx criteria 15-60% Specificity 28-92% PPV 17-40% NPV 44-74% Majority of healthy controls had pathologic results Test-retest reliability poor Does not document neuro-inflammation Hesselmark, E. J Neuroimmunol, Nov 15 (312): Treatments offered for PANS Do the Treatments for PANS work? Cognitive behavioral therapy SSRI Antibiotics- for acute flare or daily for prevention Steroids NSAIDs Plasma exchange Intravenous Immune globulin Rituximab Cytoxan Tonsillectomy, adenoidectomy Many published papers Systematic review of the literature on PANDAS, PANS treatment over 17 years 3 large consensus papers- based on expert clinical experience, no research One large survey of parents 12 treatment studies- only 4 RCTs 65 case series or case reports Total 1300 patients (90 in RCTs) -Sigra, S. Neurosci and Biobehav Rev. 86:2018.
6 Bias assessment- moderate to high risk No control groups Unclear randomization Small sample size Self selected, self reported Mixed populations- PANDAS and PANS Various levels of severity, mixed focus on outcomes for OCD vs tics Some with multiple simultaneous treatments Outcomes primarily short term Overall inconclusive for evidence of efficacy for any particular treatment -due to lack of consistent disease definition and lack of systemic research Clear adverse reactions- ranging from mild (headache, nausea, GI distress) to serious (increased psychiatric symptoms, risk of line infection and blood clots) Child Neurology Society Editorial Article Recommendations Review of the literature on PANDAS and PANS Acknowledgement of the pressure to treat even without certainty regarding etiology or efficacy Caution about the lack of consensus on this controversial dx- no accurate medical diagnostic test to rule in or rule out PANS or PANDAS Lack of data showing efficacy of any specific antibiotic or immune therapy Focus on immune tx distracts from proven therapies- CBT and SSRIs Risk of missing other neurologic disease Gilbert, Minnk, Singer. J Peds. Aug, 199: Acute onset of Psychiatric Symptoms- if healthy child, mild to moderate symptoms: no testing Acute onset Psychiatric Symptoms- if severe, disabling then stratify into 2 groups based on presence or absence of concurrent neurologic signs or symptoms -if delirium, seizures, new non-tic movement d/o, autonomic symptoms: full neurologic work up -if only psychiatric symptoms, with no concurrent neurologic symptoms: defer to psychiatry, consider based on family history, exam
7 How CAN we know when to evaluate Case #2 CANS-Childhood Acute Neuropsychiatric Symptoms -Unusually abrupt onset of severe psychiatric symptoms with concurrent other cognitive, behavioral or neurologic symptoms Likely represents multiple mechanisms -postinfectious, autoimmune, neuroinflammatory -toxic -endocrine -metabolic -vascular -psychogenic 11yo girl with GAS pharyngitis, treated with abx 1 week later behavior change emotional, anxious, difficulty sleeping (school stressors) PCP referred to child neurology for PANDAS 2 weeks later began having spells (4 in 24 hours) 3 ED visits (? non-epileptic spells) admission for expedited work up Zibordi, Euro jour Ped Neuro. 22:2018. Additional History & Clinical Exam Orobuccal Dyskinesia (YouTube video of unknown child) Withdrawn (decreased speech output), endorsed small abnormal mouth movements Type A kid, but symptoms new and atypical Normal vitals and general exam Normal neurologic exam except: Mental Status: suddenly agitated, paces around room I know what s going on, I have to go home Very rare subtle orobuccal dyskinesia (easily could be missed!)
8 EEG monitoring Differential Diagnosis 2 focal seizures (5-10 minutes each) within 1 st hour of recording pretty high burden! non-convulsive: ipsilateral nose wiping, behavioral arrest with upward eye deviation, oral and bilateral hand automatisms left temporal onset Initial EEG background left T7/P3 delta slowing and frequent spike wave discharges, normal posterior rhythm and sleep Autoimmune encephalitis (e.g. anti-nmda receptor encephalitis) Infectious encephalitis (e.g. HSV) CNS involvement of rheumatologic disease (e.g. SLE) Metabolic disorder (e.g. mitochondrial) Brain tumor Malformation of cortical development (e.g. focal cortical dysplasia) Further Evaluation Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis Brain MRI with contrast normal Serum labs no indication of infection or underlying rheumatologic disorder Lumbar Puncture 6 WBCs (lymphocyte predominant), normal protein/glucose HSV PCR negative 3 oligoclonal bands +NMDAR abs in CSF (and serum) Antibody-mediated autoimmune encephalitis (AE) Abs form against extracellular NR1 subunit of NMDA receptor Known immunologic triggers: Tumor (usually ovarian teratoma) HSV encephalitis Unknown in about 50% of patients
9 Demographics Association with HSV encephalitis Female predominance: 81% female Affects young individuals: 37% < 18 yrs (95% < 45 yrs) About 50% with a tumor, usually ovarian teratoma (not always, esp > 45) Sex ratio and detection of ovarian teratoma is age dependent Adults: largely young women, ovarian teratoma common Children < 12: sex ratio more equal, ovarian teratoma rare 20-30% of patients with HSV encephalitis can develop HSV-induced AE (most commonly anti- NMDAR encephalitis) Occurs within 2 months following HSV infection Similar clinical phenotype Armange et al, Lancet Neurology 2018 VERY IMPORTANT TO TEST FOR ANTI-NMDAR IN CASES OF HSV ENCEPHALITIS RELAPSE! Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-nmdar encephalitis: an observational cohort study. Lancet Neurology, Clinical Features Initial symptoms by age Half of children/young adults have a non-specific viral prodrome Symptoms- new onset Behavior (psychiatric) and cognitive dysfunction anxiety, agitation, bizarre behavior, hallucinations, delusions, disordered thinking Speech dysfunction Memory deficits Seizures Movement disorders: orofacial dyskinesias, choreoathetosis, dystonia, akathisia, rigidity Decreased level of consciousness Autonomic instability Sleep disturbance also common Hx in kids: my child is having tantrums and talking baby talk again (regression) - not normal! Behavior change and seizures are most common presenting symptoms in all ages Behavior more common in adults Seizures/movement disorder more common in children (< 12) Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-nmdar encephalitis: an observational cohort study. Lancet Neurology, 2013.
10 Poly-symptomatic Disease Findings in anti-nmdar encephalitis 87% developed 4 symptoms within 4 weeks 1% had only one symptom Most common: behavior/cognitive changes, memory deficits, speech disorder, seizures, movement disorder Children: movement disorder, speech disorder Adults: memory deficits and central hypoventilation Rare sxs: ataxia and hemiparesis (seen mainly in young children) Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-nmdar encephalitis: an observational cohort study. Lancet Neurology, Brain MRI often normal or shows transient FLAIR or contrast-enhancing abnormalities in cortical and subcortical regions CSF often abnormal with pleocytosis EEG usually focal or diffuse slowing More sensitive than brain MRI or CSF studies (cell count/protein) Diagnosis is confirmed with + IgG antibodies to NMDAR in CSF or serum CSF testing is important given higher sensitivity (100%) than serum (85%) What do we know about treatment? Standard Disease Treatment No prospective randomized trials Observational studies Largest study: retrospective, 501 patients (177 children) Nearly all (94%) treated with first-line immunotherapy/tumor removal 53% improved within 4 weeks Of those who didn t improve, 57% received second-line immunotherapy higher likelihood of good outcome (mrs 0-2) Tenets of treatment: responsive to immune therapy early treatment better than late if no/limited response to first-line therapy move on to second-line therapy Tumor removal Immunotherapy First-line: High-dose steroids, IVIg, plasma exchange Typically solumedrol x 5 days AND either IVIg or plasma exchange Second-line: Rituximab, cyclophosphamide Typically start with rituximab in children, but if severe consider dual-therapy Questions/challenges IVIg versus PLEX? When to move on to second-line therapy? Need novel therapies
11 Symptom Management Outcomes Goal: minimize morbidity & complications from critical illness Psychosis/agitation/delirium Delirium precautions Clonidine/dexmedetomidine Low-dose anti-psychotics only with caution (risk of NMS) Sleep disruption Melatonin, clonidine, others Movements Difficult to treat - goal is to minimize morbidity (self-harm, rhabdo), not to stop the movements Benzodiazepines, others Vigilant attention to oral care Seizures Consider avoiding levetiracetam given risk of worsening irritability Dysautonomia/hypoventilation Cardio-respiratory monitoring No difference between children and adults During hospitalization: 75% are admitted to ICU At 2 yrs, 81% of patients good outcome (mrs 0-2), 6% died Improvement up to 18 months after symptom onset Predictors of good outcome Earlier treatment with immunotherapy/tumor removal No need for ICU stay 12% relapse in first 2 yrs Titulaer et al, Treatment and prognostic factors for longterm outcome in patients with anti-nmdar encephalitis: an observational cohort study. Lancet Neurology, NEOS score (1-5) -> associated with functional status at 1 year Balu et al, Neurology 2019 Clinical Approach to Diagnosis of Autoimmune Encephalitis (Graus et al, Lancet Neurol 2016) Case #3 Goal: early treatment before ab test returns Graus criteria validated in separate cohort of children (Ho et al, Dev Med and Child Neuro 2017) 29 patients anti-nmdar, 74 other encephalitides Graus anti-nmdar criteria 90% sensitive and 96% specific Median time to meet criteria 2 weeks 10yo boy with recent onset MRI-negative focal epilepsy Presents to ED with new spells of non-stereotyped extremity movements, gait instability, and anxiety EEG: non-epileptic movements Dx: non-epileptic spells, conversion disorder (for the gait), and anxiety disorder Parents bring him back to ED couple days later with worsening anxiety ( I d rather be dead ) and episode of shaking with LOC Transferred for further evaluation/ceeg monitoring
12 Additional HX & Clinical Examination Diagnostic Evaluation/Outcome Family reported (and patient endorsed) fidgety leg movements, spells of stiffening, and withdrawal/anxiety over past few weeks -> atypical Examination: Normal vitals and general exam Normal neurologic exam except: Distressed, readily brought to tears in between spells, please help me, fluent but decreased speech output Subtle leg akathisia Several beats ankle clonus bilaterally EEG monitoring: Very frequent focal seizures Normal background initially, transitioned to diffuse slowing Brain MRI with contrast normal CSF 2 WBC, normal glucose and protein Screen for tumor - negative Fulfilled 4/6 sxs for Graus criteria empiric RX started +NMDAR ab in CSF and serum Complete recovery after first-line therapy, no relapse Take-Home Points Take-Home Points PANDAS/PANS remains a controversial diagnosis, and treatments are unproven Children with concurrent onset of acute psychiatric and neurologic symptoms deserve a full neurologic diagnostic evaluation Treatment should include evidence based psychiatric care (CBT and SSRIs) Antibiotics or immune modulation treatment should be discussed on a case by case basis, ideally based on objective findings of infection or neuro-inflammation CANS/Childhood Acute Neuropsychiatric Symptoms have a much broader differential diagnosis Anti-NMDAR encephalitis is a severe antibodymediated disease responsive to immunotherapy and clinically recognizable Young children initially present with movement disorder or seizures more often than adults, and young girls/boys nearly equally affected In all patients, important to probe about behavior/psych symptoms, changes in speech, subtle abnormal movements, spells we need to ask, listen, and promptly evaluate when indicated Goal is early therapy to improve outcome
13 Thank you For your attention! For our collaborators Emmanuelle Waubant Carla Francisco Jeffrey Gelfand Michael Wilson Bennett Leventhal Khyati Brahmbatt Josep Dalmau
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